Thiopyranopyrrolylsalicylic acids and derivatives thereof

ABSTRACT

Thiopyranopyrrolylsalicylic acids and derivatives thereof having the formula   in which X is hydrogen, hydroxy, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl nitro, amino, trifluoromethyl or cyano, R is hydroxy, alkoxy of 1 to 6 carbon atoms, amino or hydroxylamino, R1 is hydrogen, alkyl of 1 to 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms, m is 0, 1 or 2 and n is 1, 2 or 3 are disclosed to have useful anti-inflammatory and analgesic activity upon administration to mammals.

United States Patent 1191 Allen et al.

[ Nov. 4, 1975 THIOPYRANOPYRROLYLSALICYLIC ACIDS AND DERIVATIVES THEREOF [75] Inventors: Richard C. Allen, Somerville, N.J.;

Chandler R. Taylor, Jr., Mechanicsville, Va.

[73] Assignee: American Hoechst Corporation,

Bridgewater, NJ.

22 Filed: Aug. 13,1974

21 Appl. No.: 496,958

Related US. Application Data [62] Division of Ser. No, 336,920, March 1, 1973, Pat.

[52] US. Cl. 424/274 [51] Int. Cl. A61K 31/40 [58] Field of Search 424/274 Primary ExaminerStanley J. Friedman Attorney, Agent, or FirmCurtis, Morris & Safiord [57] ABSTRACT Thiopyranopyrrolylsalicylic acids and derivatives thereof having the formula (Clint k,

26 Claims, No Drawings This is a division, of application Ser. No. 336,920, filed Mar. 1, i973, now US. Pat. No. '3,86'5,839

This invention relates to thiopyranopyrrolysalicylic' acids thiopyranopyrrolylsalicylic' derivatives thereof of the formula in which X is hydrogen, hydroxy, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of l to 6 carbon atoms, phenyl nitro, amino, trifiuoromethyl or cyano', R is hydroxy, alkoxy of 1 to 6 carbon atoms, amino or hydroxylamino, R is hydrogen, alkyl of l to 6 carbon atoms or alkanoyl of l to 6 carbon atoms, m is O, l or 2 and n is l, 2 or 3, to methods of preparing such compounds, to phannaceutical compositions containing such compounds as active anti-inflammatory and analgesic agents, and to a method of treatment therewith.

To the best of our knowledge, the compounds of this invention have not heretofore been described. The only thiopyrano[4,3-b]pyrrole known to us, l,2,3,7-tetrahydrol -methyl-7,7diphenyl-4-thiopyrano[ 4,3-b ]pyrrole- 4,6-dione,,described in Angew. Chemie, Int. Ed. EngL, Vol. 6, pg, 336 (1967) is ,outside the scope of thisinvention. The compounds of the present invention are prepared by reaction of an appropriate 'y-diketone with S-aminosalicyclic acid or an appropriate derivative thereof according to the reaction scheme for reaction in a solvent inert to the reactants and the reaction product, e.g., acetic acid or ethanol, at a temperature between about and 125C. for a period of "from a few minutes to several days. It will readily be appreciated by those skilled in the art that the time and temperature necessary to complete the reaction are in- I terrelated and dependent upon the structures and compositions of the reaction components and the solvent.

in which X, R, R, m and n are as defined earlier. In a preferred embodiment of the method of this invention, the reactants are brought into contact with one another The y-diketones employed as starting materials are prepared by reaction of an appropriate thiocycloalkanone enamine with an appropriate phenacyl halide in a solvent such as benzene, toluene or dimethylformamide (DMF) for a period of from a few minutes to several days at a temperature between 0 and C, the time and temperature necessary to complete the reaction again being interrelated and dependent upon the structures and compositions of the reaction components and the solvent. The preparation of the 'y-diketones is illustrated schematically below, X, m and n being as above and hal being halogen:

' Illustrative examples of the compounds according to the present invention are:

5-( Z-phenyll ,4,6,7-tetrahydrothiopyrano[4,3-b ]pyrrol-l-yl)salicylic acid;

5-( 2-p-fluorophenyll ,4 ,6,7-tetrahydrothiopyrano[ 4 ,3- b]py'rrol-l-yl)salicylic acid;

5-( 2-m-methoxyphenyll ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrol-l-yl)salicylic acid;

methyl 5 -(2-phenyll ,4,6,7-tetrahydrothiopyrano[4,3-

b]pyrrol-lyl)salicylate;

5-( 2-o-bromophenyll ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrroll-yl) salicylamide';

5-( Z-phen yl-4,6-dihydrothieno[ 3 ,4-b pyrroll -yl) salicylic acid; and

2-acetoxy-5-( 2-phenyl- 1 ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrroll -yl )benzoic acid.

'I'hiopyrano[4,3-b]pyrrol-l-ylsalicylic acids or derivatives of Formula I, wherein X, R, R and n have the meaning as defined above and m is 0, can be oxidized to the corresponding sulfoxide or sulfone of Formula I,

wherein m is l or 2, respectively.

Thiopyrano[4,3-b]pyrrol-l-ylsalicylic acids of Formula I, wherein X, R m and n are as defined above 3 and R is hydroxy, can be converted, by standard reactions, to the corresponding esters, amides or hydroxamic acids wherein R is alkoxy of l to 6 carbon atoms, amino or hydroxylamino.

Thiopyrano[4,3-b pyrrol-l-ylsalicylic acids or derivatives of Formula 1, wherein X, R, m and n have the meaning as defined above and R is hydrogen can be converted by standard reactions to the corresponding ethers or esters wherein R is alkyl of 1 to 6 carbon atoms or alkanoyl of l to 6 carbon atoms.

The preferred compounds of the present invention are thiopyrano[4,3-b]pyrrol-l-ylsalicylic acids of the formula in which X is as defined earlier. Particularly preferred are those compounds in which X is hydrogen, or Cl, Br, F, CF CH O or phenyl substituted in the meta or para position.

The compounds of the present invention are useful as anti-inflammatory agents due to their ability to suppress inflammation in mammals. The activity of the compounds is demonstrated in the carrageenininduced rat paw edema anti-inflammatory assay [Proc. Soc. Exptl. Biol. Med., 1 l l, 544 (1962); J. Pharmacol. Exp. Ther. 141,369 (1963)]. For example, at doses of 200 mg/kg of body weight, 5-( 2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b1pyrrol- 1-yl)salicylic acid, 5- (2-m-metho xyphenyl- 1 ,4,6 ,7-tetrahydrothiopyrano[4,3-b]pyrroll -y] )salicylic acid, 5-( 2-pfluorophenyll ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrol-l-yl)salicylic acid, and 5-( Z-p-methoxyphenyll ,4,6,7-tetrahydrothiopyrano[ 4,3-b ]pyrrol+ l -yl )salicylic acid effect a 66%, 34%, 64%, and 43% inhibition of edema, respectively.

5-( Z-phenyll ,4,6,7-tetrahydrothiopyrano[4,3- b]pyrrol-l-yl)saliscylic acid and 5-(2-p-methoxyphenyll ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrroll yl)salicylic acid also exhibit at doeses of 37.5 and 50 mg/kg, respectively, an approximately 50% inhibition of 2-pheny1-1,4-benzoquinone-induced writhing in mice, a standard assay for analgesia [Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)]. For comparison, aspirin, a known anti-inflammatory and analgesic agent, effects a 53% inhibition of edema at a dose of 128 mg/kg and a 34% inhibition of 2-phenyl-1,4-benzoquinone-induced writhing at a dose of 60 mg/kg. These data illustrate that the thiopyranopyrrolylsalicylic acids and related compounds of this invention are useful for the suppression of inflammation and pain in mammals when administered in amounts ranging from 1 to about 200 mg per kg of body weight per day.

The compounds of the present invention may be administered by any convenient route such as orally, in-

' tramuscularly, intravenously, subcutaneously, or intraperitoneally. The preferred route of administration is between 7% to about of the weight of the unit. The

amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 200 milligrams of active compound.

The tablets, pills, capsules, troches, and the like may also contain the following ingredients: a binder such as gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, potato starch and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or both. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent, and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions must be pharrnaceutically pure and non-toxic in the amounts utilized.

The invention is further illustrated by the following examples.

EXAMPLE l a. 5,6-Dihydro-4-( l-pyrrolidinyl)-2H-thiopyran A solution of 103 g (0.9 mol) of tetrahydrothiopyran- 4-one, g 1.33 mol) of pyrrolidine, and 1 liter of anhydrous benzene was heated under reflux in a nitrogen atmosphere for 2 hrs. until the theoretical amount of water was collected in a water trap. The solvent was distilled and the residue fractionated under reduced pressure to provide 105 g of colorless liquid, b.p. 124C. at 0.01 mm.

b. 3-Phenacyl-2,3,5,6-tetrahydrothiopyran-4-one A solution of 56.3 g (0.28 mol) of phenacyl bromide in ml of DMF was added, in the course of 20 minutes and under a nitrogen atmosphere, to a cooled, stirred solution of 41.6 g (0.28 mol) of 5,6-dihydro-4- (l-pyrrolidinyl)-2H-thiopyran in 300 ml of anhydrous DMF. After 2 hours, the solution was diluted with water and extracted with chloroform; the chloroform extracts were washed with water, dried and concentrated. Crystallization from ethanol gave 43 g of solid; mp. l0l.5-l03.5C.

c. 5-( Z-Phenyll ,4,6,7-tetrahydrothiopyrano[4,3-b1pyr rol-l-yl)salicylic acid A stirred suspension of 13.7 g (0.06 mol) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one, 9.0 g (0.06

mol) of S-aminosalicylic acid, and 60 ml of glacial acetic acid was refluxed under a nitrogen atmosphere for 1 hours. The reaction mixture was cooled to room temperature and the solid removed by filtration. 5

Recrystallization from acetic acid and acetonitrile yielded 10.4 g (50%) of crystals; m.p. 220225.5C. (dec.).

Calc. for C l-1 NO S: 68.35% C; 4.88% H; 3.99% N; Found 68.03% C; 4.83% H; 4.38% N.

EXAMPLE 2 a. 3-(p-Bromophenacyl)-2.3 ,5 ,6-tetrahydrothiopyran- 4-one b. 5-( 2-p-Bromopheny1- 1 ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrol-1-yl)salicylic acid A stirred suspension of 4.0 g (0.013 mol) of 3-(pbromphenacyl)-2,3,5 ,6-tetrahydrothiopyran-4-one and 1.95 g (0.013 mol) of 5-aminosalicylic acid in ml of glacial acetic acid was heated to reflux under nitrogen for 1 hour, cooled and filered to provide 5.2 g (94%) of crystals, m.p. 260-262C. (dec.).

Calc. for C l-l BrNO S: 55.82% C; 3.75% H; 3.26% N; Found 55.78% C; 3.78% H; 3.16% N.

EXAMPLE 3 a. 3-(p-Fluorophenacyl )-2,3 ,5 ,6-tetrahydropyran-4-one To a cooled, stirred solution of 16.9 g (0.1 mol) of 5,6-dihydro-4-( 1-pyrrolidinyl)-2H-thiopyran in 100 ml. of anhydrous DMF was added, in the course of 40 minutes and under nitrogen, a solution of 21.7 g (0.1 mol) of a-bromo-p-fluoroacetophenone in 50ml of DMF. After 6 hrs. at room temperature, the mixture was worked up as described in Example 1a. Yield 10.6 g of crystals; m.p. 1l1.5-1l3.5C.

b. 5-( 2-p-Fluorophenyl- 1 ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrol- 1-yl)sa1icylic acid 5.0 g (0.02 mol) of 3-(p-fluorophenacyl)-2,3,5,6-tetrahydropyran-4-one and 3.0 g (0.02 mol) of 5- aminosalicylic acid in 20 ml. of glacial acetic acid were reacted as described in Example 2b for V2 hour, cooled and filtered to provide 6.6 g (90%) of crystals. After recrystallization from ethanol, m.p. 240-243C. (dec.).

Calc. for C H FNO S: 65.03% C; 4.37% H; 3.79% N; Found: 64.88% C; 4.43H; 3.67% N.

EXAMPLE 4 a. 3-(p-Methoxyphenacyl )-2,3 ,5 ,6-tetrahydrothiopyran- 4-one 16.9 g (0.1 mol) of 5,6-dihydro-4-(l-pyrrolidinyl- 2H-thiopyran dissolved in ml. of anhydrous DMF and 23.2 g (0.1 mol) of a-bromo-p-methoxyacetophenone in 50 ml. of DMF were reacted as described in Example 3a and the reaction mixture was worked up as described in Example 1a. After crystallization of the crude product from methanol and then from acetic acid, m.p. l23125C.

b. 5-( 2-p-Methoxyphenyl- 1 ,4,6,7-tetrahydrothiopyrano[4.3-b]pyrrol-1-yl)salicylic acid 5.0 g (0.02 mol) of 3-(p-methoxyphenacy1)-2,3,5,6- tetrahydrothiopyran-4-one and 2.9 g (0.02 mol) of 50 aminosalicylic acid in 25 ml. of glacial acetic acid were reacted as described in Example 2b for 2 hours, the suspension was filtered while hot and the filtrate was cooled and again filtered to provide 6.1 g of solid. After recrystallization from acetonitrile, m.p. 2l0-212C. (dec.).

Calc. for C H, NO S: 66.12% C; 5.02% H; 3.67% N; Found 2 66.02% C; 5.10% H; 3.99% N.

EXAMPLE 5 a. 3-(p-Chlorophenacyl -2,3 ,5 ,6-tetrahydrothiopyran- 4-one 16.9 g (0.1 mol) of 5,6-dihydro-4-(l-pyrrolidinyl)- 2l-l-thiopyran dissolved in 100 ml. of anhydrous DMF and 23.4 g (0.1 mol) of a-bromo-p-chloroacetophenone in 50 ml. of DMF were reacted as described in Example 3a and the reaction mixture was worked up as described in Example 2a., Recrystallization from ethanol provided 12.2 g of crystals; m.p. 78-81C.

b. 5-( 2-p-Chlorophenyl- 1 ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrroll-yl)salicylic acid 5.0 g (0.02 mol) of 3-(p-chlorophenacyl)-2,3,5,6-tetrahydrothiopyrano-4-one and 2.9 g (0.02 mol) of 5- aminosalicylic acid in 20 ml. ofzglacial acetic acid were reacted as described in Example 2b for hrs., cooled and filtered to provide 5 .3 g of crystals. After recrystallization from acetic acid, m.p. 250253C. (dec.).

Calc. for C H ClNO S: 62.25% C; 4..8% H; 3.63% N; Found 61.93% C; 4.39% H; 3.51% N. 4.39%

EXAMPLE 6 a. 3-( m-Trifluoromethylphenacyl')-2,3 ,5 ,6-tetrahydrothiopyran-4-one 20 g (0.12 mol) of 5',6-dihydro-4-(l-pyrrolidinyl)- 2l-l-thiopyran dissolved in ml. of anhydrous DMF and 32.6 g (0.12 mol) of a-bromo-m-trifluoromethylacetophenone in 10 ml. of DMF were reacted as described in Example 3a for 2 hrs. and the reaction mixture was worked up as described in Example 2a. 1 1.7 g of an oily product was obtained. IR and NMR spectra were consistent with the assigned structure. I

b. 2-m-Trifluoromethylpheny1- l ,4,6,7-tetrahydrothiopyrano-[4,3-b]pyrrol-1-yl)salicylic acid 5.0 g (0.017 mol) of 3-(m-trifluoromethylphenacyl)- 2,3,5,6-tetrahydrothiopyran-4-one and 2.53 g (0.017 mol) of S-aminosalicylic acid in 20 ml. of glacial acetic acid were reacted as described in Example 2b and worked up as described in Example 4b to provide 4.0 g g (58%) of crystals. After recrystallization from acetonitrile, m.p. 223.5226C. (dec.).

Calc. for C ,H F NO S: 60.14% C', 3.85% H; 3.34% N; Found: 59.84% C; 3.90% H; 3.61% N.

EXAMPLE 7 a. 3-(m-Methoxyphenacyl)-2,3,5,6-tetrahydrothiopyran- 4-one 16.9 g (0.1 mol) of 5,6-dihydro-4-(l-pyrrolidinyl)- 2H-thiopyran in 100 ml. of anhydrous DMF and 22.9 g (0.1 mol) of a-bromo-m-methoxyacetophenone in 50 ml. of DMF were reacted as described in Example 3a for 3 hrs. and the reaction mixture was worked up as described in Example 2a. Recrystallization from ethyl acetate provided 10.8 g of crystals; m.p. 63-66C.

b. 5-( 2m-Methoxyl ,4,6,7-tetrahydrothiopyrano[4,3- b]pyrrol-1(-yl)salicylic acid 4.0 g (0.015 mol) of 3-(m-methoxyphenacyl-2,3,5,6- tetrahydrothiopyran-4-one and 2.3 g (0.015 mol) of 5- aminosalicylic acid in ml. of glacial acetic acid were reacted as described in Example 2b for 3 hrs. and filtered. The filtrate was cooled, stirred for 1 hr. and again filtered. 5.4 g of solids were obtained. Afterrepeated recrystallization from ethyl acetate, pale yellow crystals were obtained; m.p. 2l42l5.5 (dec.).

Calc. for C H NO S: 66.12% C; 5.02% H; 3.67% N; Found 66.07% C; 5.08H; 3.65% N.

EXAMPLE 8 a. 3-( p-Phenylphenacyl )-2,3 ,5 ,6-tetrahydropyran-4-one b. 5-( Z-p-Biphenylyll ,4,6,7-tetrahydrothiopyrano[ 4,3-

' b]pyrroll-yl )salicylic acid 3.5 g (0.01 mol) of 3-(p-phenylphenacyl)-2,3,5,6- tetrahydropyran-4-one, 1.72 g (0.01 mol) of 5- aminosalicylic acid and 15 ml. of glacial acetic acid were heated under reflux under nitrogen for 3 hours, filtered, cooled and filtered again to provide 3 g of product which was chromatographed on silica gel with a chloroform-methanol mixture and recrystallized from acetonitrile to give 1.5 g of crystals, m.p. 230239C. Calc. for C H NO SJ/2CH CN: 72.38% C; 5.06% H; 4.69N; Found 71.99% C; 5.07% H; 4.70% N.

I EXAMPLE 9 i w a.

5 ,6-Dihydro-4-( 1-pyrrolidinyl)-2H-thiopyran- 1 l-dioxide A mixture of 18.0 g (0.12 mol) of tetrahydrothiopyran-4-one-1,l-dioxide, 13.0 g (0.18 mol) of pyrrolidine, 50g of 5A molecular sieves, and 400 ml. of anhydrous benzene was shaken for 3.5 hrs. and filtered. The

filtrate was concentrated under reduced pressure to a gummy solid.

b. 3-Phenacyl-2,3 ,5 ,6-tetrahydrothiopyran-4-one-1 1 dioxide 23.0 g (0.11 mol) of 5,6-dihydro-4(l-pyrrolidinyl)- 2H-thiopyran-1,1-dioxide in ml. of anhydrous DMF and 22.8 g (0.1 1 mol) of phenacyl bromide were reacted as described in Example 3a for 18 hrs. and the reaction mixture was worked up as described in Example 2a, the eluent being a 99:1 benzene-methanol mixture. The crude solid was recrystallized from methanol to give colorless crystals, m.p. 157.5-159C.

5-(5 ,5-Dioxo-2-phenyl- 1 ,4,6,7-tetrahydrothiopyrano[4,3-b]pyrro1 1-y1)sa1icylic acid 4.0 g (0.015 mol) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one-1,1-dioxide and 2.3 g (0.015 mol) of 5-aminosalicy1ic acid in 15 ml. of glacial acetic acid were reacted as described in Example 2b for 1.5 hrs. and filtered to provide 5.3 g (92%) of an off-white solid. Recrystallization from l-butanol gave colorless crystals, mp. 283C. (dec.).

Calc. for C H NO S: 62.65% C; 4.47% H; 3.65% N; Found 62.80% C; 4.72% H; 3.55% N. 62.65% 4.47% 3.65%

EXAMPLE l0 5-(5-oxo-2-phenyll ,4,6,7-tetrahydrothiopyrano[4,3- b]pyrrol-1-yl)salicylic acid To a cold (0C) stirred solution of 7.5 g (0.02 mol) of 5-(2-phenyl- 1 ,4,6,7-tetrahydrothiopyrano-[4,3-b]pyrrol-l-yl)salicylic acid (prepared according to Example 10) and 375ml. of ethanol was added, under nitrogen, a solution of 4.55-g (0.02 mol) of sodium metaperiodate in 100 ml. of water. The mixture was stirred for 18 hrs., diluted with chloroform, and filtered. The layers were separated and the organic phase was washed with water, dried and concentrated to a solid. Two recrystallizations from methanol provided 2.4 g of crystals, m.p. 199201.5C (dec.).

Calc. for C H NO S: 64.78% C; 4.83% H; 3.73% N; Found 64.74% C; 4.75% H; 4.12% N.

We claim:

1. A method of treating inflammation and pain which comprises administering to a mammal an effective amount of an active compound of the formula COR in which X is hydrogen, hydroxy, halogen, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, phenyl, nitro, amino, trifiuoromethyl or cyano, R is hydroxy, alkoxy of l to 6 carbon atoms or amino, R is hydrogen, alkyl of l to 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms, and m is 0, l or 2.

2. The method of treatment defined in claim 1 wherein X is hydrogen, R is hydroxy, R is hydrogen and m is 2.

3. The method of treatment defined in claim 1 wherein X is hydrogen, R is hydroxy, R is hydrogen and m is l.

4. A method of treatment as defined in claim 1 in which the active compound has the formula COOH wherein X has the meaning defined in claim 1.

5. A method of treatment as defined in claim 4 wherein X is hydrogen, fluoro, chloro, bromo, methoxy, trifiuoromethyl or phenyl.

6. A method of treatment as defined in claim 5 wherein X is hydrogen.

7. The method of treatment defined in wherein X is p-bromine.

8. The method of treatment defined in wherein X is p-fluorine.

9. The method of treatment defined in wherein X is p-chlorine.

10. The method of treatment defined in wherein X is p-methoxy.

11. The method of treatment defined in wherein X is m-methoxy.

12. The method of treatment defined in wherein X is p-trifiuoromethyl.

13. The method of treatment defined in wherein X is p-phenyl.

14. An orally administrable composition for treating inflammation and pain which consists essentially of a pharmaceutically acceptable carrier and from to 200 mg per dosage unit of an active compound of the formula claim claim claim claim claim claim UIUIUIUIUIUIUI claim in which X is hydrogen, hydroxy, halogen, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, phenyl, nitro amino, trifiuoromethyl or cyano, R is hydroxy, alkoxy of l to 6 carbon atoms or amino, R is hydrogen, alkyl of l to 6 carbon atoms or alkanoyl of l to 6 carbon atoms, and m is O, 1 or 2.

15. An orally administrable composition as defined in claim 14 in which X is hydrogen, R is hydroxy, R, is hydrogen, and m is 2.

16. An orally administrable composition as defined in claim 14 in which X is hydrogen, R is hydroxy, R is hydrogen and m is l.

17. An orally administrable composition as defined in claim 14 in which the active compound is a compound of the formula L i m x I COOH wherein X has the meaning defined in claim 14.

18. An orally administrable composition as defined in claim 17 in which X is hydrogen, fluoro, chloro, bromo, methoxy, trifiuoromethyl or phenyl.

19. An orally administrable composition as defined in claim 17 in which X is hydrogen. 1

20. An orally administrable composition as defined in claim 17 in which X is p-bromine.

' 21. An orally administrable composition as defined in claim 17 in which X is p-fluorine.

22. An orally administrable composition as defined in claim 17 in which X is p-chlorine.

23. An orally administrable composition as defined in claim 17 in which X is p-methoxy.

24. An orally administrable composition as defined in claim 17 in which X is m-methoxy.

25. An orally administrable composition as defined in claim 17 in which X is p-trifluoromethyl.

26. An orally administrable composition as defined in claim 17 in which X is p-phenyl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION 5 PATENT NO. 3,917,842

DATED November 4, 1975 V I RICHARD c. ALLEN, ct a1 It is certified that error appears in the above-identified patent and that said Letters Patent 3 are hereby corrected as shown below:

Column 3, line 5: "[4,3-b pyrrol" should read --[4 ,3-b]pyrrol-;

Column 6, line 50: "1/2" should read --3/ r--;

Column 6, line 54: delete last occurrence of "4. 397";

Column 7, line 30: "-l(-yl)" should read l-yl) Column 8, lines 37 and 38: delete "62.65% 4.47% 3.65%".

! Signed and Scaled this sixth Day of April1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting ()ffiver Commissioner nj'lan'nls and Trademarks UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 2 3 917 42 DATED November 4, 1975 V I RICHARD c. ALLEN, et a1 It is certified that error appears in the ab0veidentified patent and that said Letters Patent are hereby corrected as shown below:

Column 3, line 5: "[4,3-b pyrrol" should read --[4 ,3b]pyrrol;

Column 6, line 50: "1/2" should read -3/4 Column 6, line 54: delete last occurrence of "4. 397";

Column 7, line 30: "-l(-yl)" should read lyl) Column 8, lines 37 and 38: delete "62.65% 4.47% 3.65%".

Signed and Sealed this sixth Day of April1976 [SEAL] Arrest:

RUTH C. MASON c. MARSHALL DANN 8 ff Commissioner uflarents and Trademarks 

1. A METHOD OF TREATING INFLAMMATION AND PAIN WHICH COMPRISES ADMINISTERING TO A MAMMAL AN EFFECTIVE AMOUNT OF AN ACTIVE COMPOUND OF THE FORMULA
 2. The method of treatment defined in claim 1 wherein X is hydrogen, R is hydroxy, R1 is hydrogen and m is
 2. 3. The method of treatment defined in claim 1 wherein X is hydrogen, R is hydroxy, R1 is hydrogen and m is
 1. 4. A method of treatment as defined in claim 1 in which the active compound has the formula
 5. A method of treatment as defined in claim 4 wherein X is hydrogen, fluoro, chloro, bromo, methoxy, trifluoromethyl or phenyl.
 6. A method of treatment as defined in claim 5 wherein X is hydrogen.
 7. The method of treatment defined in claim 5 wherein X is p-bromine.
 8. The method of treatment defined in claim 5 wherein X is p-fluorine.
 9. The method of treatment defined in claim 5 wherein X is p-chlorine.
 10. The method of treatment defined in claim 5 wherein X is p-methoxy.
 11. The method of treatment defined in claim 5 wherein X is m-methoxy.
 12. The method of treatment defined in claim 5 wherein X is p-trifluoromethyl.
 13. The method of treatment defined in claim 5 wherein X is p-phenyl.
 14. An orally administrable composition for treating inflammation and pain which consists essentially of a pharmaceutically acceptable carrier and from 10 to 200 mg per dosage unit of an active compound of the formula
 15. An orally administrable composition as defined in claim 14 in which X is hydrogen, R is hydroxy, R1 is hydrogen, and m is
 2. 16. An orally administrable composition as defined in claim 14 in which X is hydrogen, R is hydroxy, R1 is hydrogen and m is
 1. 17. An orally administrable composition as defined in claim 14 in which the active compound is a compound of the formula
 18. An orally administrable composition as defined in claim 17 in which X is hydrogen, fluoro, chloro, bromo, methoxy, trifluoromethyl or phenyl.
 19. An orally administrable composition as defined in claim 17 in which X is hydrogen.
 20. An orally administrable composition as defined in claim 17 in which X is p-bromine.
 21. An orally administrable composition as defined in claim 17 in which X is p-fluorine.
 22. An orally administrable composition as defined in claim 17 in which X is p-chlorine.
 23. An orally administrable composition as defined in claim 17 in which X is p-methoxy.
 24. An orally administrable composition as defined in claim 17 in which X is m-methoxy.
 25. An orally administrable composition as defined in claim 17 in which X is p-trifluoromethyl.
 26. An orally administrable composition as defined in claim 17 in which X is p-phenyl. 